This proposal outlines a series of experiments designed to test and refine our understanding of the mechanisms by which the developing tissues precisely patterned. Such precision is essential to the normal human development, and analyzing the means by which such patterning arises is essential to both our understanding of normal fetal development, and for developing therapies for the recovery from disease and injury. The ability of researchers to experimentally analyze development in vertebrates is limited, however, by the complexity of the vertebrate genome and fetus. This proposal therefore outlines an ongoing seriesof experiments that analyze these problems in the developing appendages of the fruitly, Drosophila melanogaster. In the fruitfly wing, specific tissues arise in an extremely stereotyped fashion from a single layer of epithelial cells. Not only is this system simple, but the genetic and molecular tools available for work on Drosophila are unmatched by any other animal system. We will use a combination of genetic, histochemical and molecular techniques to analyze the developmental bases of the stereotyped neuronal development found in Drosophila. Our analyses include testing the roles of a number of known genes and signaling pathways, and searching for novel genes critical to the patterning process. Our first aim is to analyze the role of the secreted protein Shifted, a homolog of human Wnt Inhibitory Factor-1, and how it intercts with Hedgehog signaling during the induction of cells along compartment boundaries. Our second aim is examine a novel signaling mechanism by which two unusual protocadherins, Fat and Dachsous, regulate the growth and proximal-distal patterning.